1. Field of the Invention
The present invention relates to 20-fluoropregna-5,17(20)-diene-3xcex2,21-diol, 20-fluoro-pregna-5,17(20)-dien-3xcex2-ol and related compounds, to processes for their preparation, and to compositions incorporating these compounds as well as the use of these compounds in the treatment of conditions which would be affected by inhibition of C17,20 lyase and/or 5xcex1-reductase, including androgen and estrogen mediated or dependent disorders, such as, for example benign prostatic hyperplasia; dihydrotestosterone-mediated disorders such as, for example, acne; estrogen dependent breast cancer and androgen mediated prostatic cancer. The present invention provides a novel series of compounds which also disable the operation of C17-hydroxylase; thus, disorders that are characterized by an oversynthesis of cortisol can also be treated by the compounds of the invention. For example, hypokalemia, metabolic alkalosis, polydipsia, polyurea, Cushing""s syndrome and hypertensive conditions.
2. Description of the Art
The enzyme steroid C17,20 lyase cleaves the 17-20 carbon-carbon bond in steroids having a two carbon side chain at the 17xcex2-carbon position to form important precursor molecules for the formation of testosterone, 5xcex1-dihydrotestosterone and the estrogens, principally estrone and estradiol. Compounds which inhibit this enzyme would thus serve to inhibit the formation of the indicated precursors and thereby be useful in the treatment of various androgenic as well as estrogenic disorders. A treatment incorporating such enzymatic inhibitors is not limited to the origin of the precursor molecule, such as various organ ablation techniques which are currently known. For example, while orchiectomy will effectively reduce gonadal androgen, it will have not have significant effect upon adrenal androgen production. Moreover, such an enzymatic treatment is a much more focused treatment in that it is directed to the immediate hormonal imbalance believed responsible for the condition, as opposed to a broad spectrum remedy which not only affects the particular symptom, but causes permanent endocrine deficits necessitating life-long dependency on replacement therapy.
It is further known that certain types of breast cancers are estrogen dependent. Adrenalectomy, ovariectomy and hypophysectomy have been employed as well as non-surgical techniques resulting in tumor regressions. It has been shown that human patients with advanced breast cancer, who are administered estrogen biosynthesis enzyme inhibitors, show dramatically reduced plasma estradiol levels and improved therapeutic effects, at least as effective as adrenalectomy. [Van Wauve, J. and Janssen, P. A. J., J. Med. Chem. 1989, 32, 2231-2239].
Prostatic cancer, or neoplastic tissue disorders which originate in the parenchymal epithelium of the prostate, is one of the most common malignancies among men, and exhibits one of the highest cancer-specific deaths of all malignant carcinomas. It is known that patients with metastatic prostate cancer respond positively to hormonal therapy. It is reported by Cookson and Sarosdy that androgen ablation has had a positive, beneficial response for as high as 60% to 80% of all patients tested. [Cookson, C. S. and Sarosdy, M. F., South Med. J. 1994, 87, 1-6].
More specifically, C17,20 lyase inhibitors would be useful in the treatment of hormonal dependent prostatic carcinorna, prostatic hyperplasia, virilism, congenital adrenal hyperplasia due to 21-hydroxylase deficiency, hirsutism, hormonal dependent breast cancer, polycystic ovarian syndrome correlated with elevated C17,20 lyase activity as well as other neoplastic tissue disorders such as endometrial, hepatocellular and adrenal carcinomas.
The enzyme steroid 5xcex1-reductase, present in mammalian tissues including skin, male genitalia and the prostate, catalyzes the conversion of testosterone (17xcex2-hydroxyandrost-4-en-3-one) into dihydrotestosterone or DHT (17xcex2-hydroxy-5xcex1-androstan-3-one), which is also known as stanolone. DHT is a more potent androgen than testosterone, and acts as an end-organ effector in certain tissues, particularly in mediating growth. DHT formation can occur in certain tissues themselves by the action of 5xcex1-reductase. The conversion of testosterone to DHT itself can be associated with various androgenic disorders, especially when DHT levels build up to excessive amounts. For example, high levels of DHT in the skin has been associated in the pathogenesis of acne, including acne vulgaris. In the treatment of androgen mediated or androgen dependent disorders, such as acne, benign prostatic hyperplasia and prostatic cancer, including hormonal dependent carcinoma, the inhibition of DHT would be highly desirable.
Agents that have the ability to inhibit both C17,20 lyase and 5xcex1-reductase would not only inhibit DHT production, but also testosterone formation. In inhibiting the principal androgenic steroidal hormones, such compounds would have enhanced utility in the treatment of androgen mediated or dependent disorders.
The enzyme C17 hydroxylase catalyzes the C17 hydroxylation of steroid substrates during the biosynthesis of cortisol. As C17,20 lyase and C17 hydroxylase are the same active site of the same enzyme, the inhibition of one usually results in the inhibition of the other. Cortisol excess results in a syndrome characterized by hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing""s syndrome and hypertensive conditions. Inhibition of cortisol synthesis via C17 hydroxylase would, therefore, have a beneficial therapeutic effect for the treatment of these disorders or conditions.
More particularly, the present invention is directed to a group of compounds, and to their pharmaceutically acceptable salts, of the formula: 
wherein:
R1 is H or C1-4 alkyl;
R2 is H or C1-4 alkyl;
R3 is H, chloro, nitro, amino or C1-4 alkyl;
R4 is H or C1-4 alkyl;
R5 is H or C1-4 alkyl;
R6 is H or methyl;
R7 is H or methyl;
R8 is H or methyl;
R9 is H or methyl;
or R8 and R9 taken together is oxo;
R10 is H or methyl;
R11 is H;
R12 is hydroxy;
or R11 and R12 taken together is oxo;
X is H, hydroxy or methoxy;
with the proviso that when:
a) R11 is H and R12 is hydroxy, bond C4,5 is a single bond, bond C5,6 is a double bond and bond C15,16 is optionally a single bond or a double bond, and
b) R11 and R12 taken together is oxo, bond C4,5 is a double bond, bond C5,6 is a single bond, and bond C15,16 is a single bond.
Another embodiment of the invention provides use of the compounds of the invention as inhibitors of C17,20 lyase and 5xcex1-reductase for the treatment of androgen or estrogen mediated or dependent disorders such as breast cancer, polycystic ovarian syndrome, prostatic hyperplasia, prostatic cancer, virilism, hirsutism, and acne.
In another embodiment, the invention provides use of the compounds of the invention for the treatment of Cushing""s syndrome.
In yet another embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
In another embodiment, the compounds of the invention may be administered in combination with other effective treatments for enhanced therapeutic effect. For example, in the treatment of androgen-dependent disorders, including prostatic cancer, flutamide, a known androgen receptor antagonist, may be used in combination with compounds of the invention.
A preferred embodiment of the invention are compounds wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and X are hydrogen, R10 is methyl, R12 is hydroxy, bond C4,5 and bond C15,16 are each a single bond and bond C5,6 is a double bond.
A most preferred embodiment of the invention are compounds wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R11 are hydrogen, R10 is methyl, X and R12 are each hydroxy, bond C4,5 and bond C15,16 are each a single bond and bond C5,6 is a double bond.
As used herein, the term xe2x80x9cC1-4 alkylxe2x80x9d means any straight or branched chain alkyl radical of one to four carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or t-butyl.
As used herein, the following structural designations as used in the formulas shall have the following meanings:  is defined as a bond below the plane of the steroid (the xcex1-face).  is defined as a bond above the plane of the steroid (the xcex2-face).  is defined as a cis or trans bond (or mixture of the two) whose stereochemistry is not defined.  is defined as an optional double bond.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to apply to any salt, whether previously known or future discovered, that is used by one skilled in the art that is a non-toxic organic or inorganic addition salt which is suitable for use as a pharmaceutical. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium or magnesium hydroxides; ammonia and aliphatic, cyclic or aromatic amines such as methylamine, dimethylamine, triethylamine, diethylamine, isopropyldiethylamine, pyridine and picoline. Illustrative acids which form suitable salts include inorganic acids such as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric and like acids, and organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and like acids, and organic sulfonic acids such as methanesulfonic and p-toluenesulfonic acids.
As used herein xe2x80x9cstereoisomerxe2x80x9d is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
As used herein, the term xe2x80x9ceffective inhibitory amount,xe2x80x9d is such an amount wherein an enzyme inhibitory effect is achieved to cause a therapeutic effect in a patient. The exact amount of compound to be administered can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing the results obtained under analogous circumstances. Factors significant in determining the dose include: the species of animal, the animal""s size, age and general health; the specific disease or disorder involved, the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. That said, the exact amount employed may vary over a wide range, for example, from about 0.625 to 200 mg/kg of body weight per day, preferably from about 5 to 100 mg/kg of body weight per day.
xe2x80x9cTreatxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any treatment, including but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or to preventing or slowing the appearance of symptoms and progression of the named disease, disorder or condition.
As described herein, the term xe2x80x9cpatientxe2x80x9d refers to a warm blooded animal such as a mammal which is afflicted with a particular disease, disorder or condition. It is explicitly understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.
In practicing the methods of this invention, the active ingredient is preferably incorporated into a composition containing a pharmaceutical carrier, although the compounds are effective and can be administered, in and of themselves. The term xe2x80x9cpharmaceutical carrierxe2x80x9d refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for administration, and which are substantially nontoxic and nonsensitizing under conditions of use. The exact proportion of these excipients are determined by the solubility and chemical properties of the active compound, the chosen route of administration as well as standard pharmaceutical practice. That said, the proportion of active ingredient can vary from about 5 to 90% by weight.
The pharmaceutical compositions of the invention are prepared in a manner well known in the pharmaceutical arts. The carrier or excipients may be a solid, semisolid or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral, inhalation, parenteral or topical use, and may be administered to the patient in the form of tablets, capsules, suspensions, syrups, aerosols, inhalants, suppositories, salves, powders, solutions and the like. As used herein, the term xe2x80x9cpharmaceutical carrierxe2x80x9d means one or more excipients.
In preparing formulations of the compounds of the invention, care should be taken to ensure bioavailability of an effective inhibitory amount, including oral, parenteral and subcutaneous routes. For example, effective routes of administration may include subcutaneously, intravenously, transdermally, intranasally, rectally, vaginally and the like including release from implants as well as direct injection of the active ingredient and/or composition directly into the tissue or tumor sites. Suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington: The Science and Practice of Pharmacy, 19th edition, Volumes 1 and 2, 1995, Mack Publishing Co., Easton, Pa., U.S.A., which is herein incorporated by reference.
For oral administration, the compounds can be formulated into solid or liquid preparations, with or without inert diluents or edible carriers, such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions. The capsules, pills, tablets, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth; excipients such as starch or lactose, disintegrating agents such as alginic acid, corn starch and the like; lubricants such as stearic acid, magnesium stearate or Sterotex(copyright), (Stokely-Van Camp Inc., Indianapolis, Ind.) glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; and flavoring agents such as peppermint, methyl salicylate or fruit flavoring. When the dosage unit form is a capsule, it may also contain a liquid carrier such as polyethylene glycol or a fatty oil. Materials used should be pharmaceutically pure and nontoxic in the amounts used.
For parenteral administration, the compound may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water-in-oil or without the addition of a surfactant and other pharmaceutically acceptable excipients. Illustrative oils which can be employed in the preparations are those of petroleum, animal, vegetable or synthetic origin such as, for example, peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols, such as propylene glycol are preferred liquid carriers, particularly for injectable solutions. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of inert plastic or glass.
The solutions or suspensions described above may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetra-acetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
The compounds can be administered in the form of a cutaneous patch, a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers and synthetic silicones. Further information on suitable pharmaceutical carriers and formulation techniques are found in standard texts such as Remington: The Science and Practice of Pharmacy, 19th edition, Volumes 1 and 2, 1995, Mack Publishing Co., Easton, Pa., U.S.A.
The compounds of the present invention can be prepared by processes analogous to those known in the art. Reaction schemes A to O and the corresponding descriptive text describe the preparation of the various compounds of the invention. The methods disclosed and examples are provided for illustration purposes and in no way limit the scope of the present invention. Alternative reagents, reaction conditions, and other combinations and permutations of the steps herein described to arrive at individual compounds are readily apparent to one of ordinary skill in the art.
DIBALH=diisobutylaluminum hydride; DMAP=4-dimethylaminopyridine; DMF=dimethylformamide; LAH=lithium aluminum hydride; LHMDS=lithium hexamethyldisilazide; NBS=N-bromosuccinimide; PCC=pyidinium chlorochromate; PDC=pyridinium dichromate; Pyr. SO3=sulfur trioxide pyridine complex; TBAF=tetrabutylammuonium fluoride; TBDMS=t-butyldimethyl-silyl; TEA=triethylamine; THF=tetrahydrofuran; Ac2O=acetic anhydride; TsOH=tosic acid (p-toluenesulphonic acid); "xgr"=designation for undefined geometry about a double bond, g=grams; mmol=millimole, mL=milliliters; bp=boiling point; mp=melting point; xc2x0 C.=degrees Celsius; mm Hg=millimeters of mercury; xcexcL=microliters, xcexcg=micrograms; xcexcM=micromolar; mM=millimolar; xcexcCi=microcurie; M=molar; NADPH=hydrogenated nicotinamide adenine dinucleotide phosphate; DMSO=dimethylsulfoxide; EDTA=ethylenediaminetetraacetic acid; HPLC=high performance liquid chromatography. 
The unsubstituted steroid-5-en-3-ols of this invention may be prepared by as depicted in Scheme A. Protecting the hydroxyl group of dehydroepiandrosterone (A1) by reaction with t-butyldimethylsilyl chloride gives silyl ether A2. Wittig reaction on the C17 ketone of A2 with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with a suitable base such as lithium hexamethyldisilazide gives vinyl fluoride ester A3 as a mixture of E- and Z-isomers. A suitable base in this instance is any base that will function to form a ylid by reaction with triethyl 2-fluoro-2-phosphonoacetate such as, for example, lithium hexamethyldisilazide, alkyl lithium bases such as t-butyllithium, potassium t-butoxide and the like. Separation of the isomers is possible, but difficult at this point, so it is usually done after the next step. Reduction of ester A3 is accomplished with a suitable reducing agent such as diisobutylaluminum hydride in dichloromethane to give a mixture of hydroxymethyl vinyl fluorides which are separated into the individual E- and Z-isomers A4 and A5, respectively. Removal of the silyl protecting group of E-olefin A4 with tetrabutylammonium fluoride gives diol A6. Similarly, the silyl protecting group of Z-olefin A5 is removed to yield diol A9. Further reduction of alcohol A4 or A5 using sulfur trioxide pyridine complex in tetrahydrofuran followed by treatment with lithium aluminum hydride gives the corresponding C21 deoxy derivatives A7 and A10, respectively. Removal of the silyl protecting groups from A7 and A10 as described above gives alcohols A8 and A16, respectively.
The C21, substituted steroid-5-en-3-ols of this invention may be prepared following the methodology depicted in Scheme B. Using the mixture of vinyl fluoride esters A3 as starting material, the following transformations can be accomplished. The silyl group of A3 is removed using tetrabutylammonium fluoride giving alcohol B12. The latter is oxidized with pyridinium chlorochromate (see Parish, E. J. and Honda, H. Syn. Commun., 1990, 20, 1167-1174) to give conjugated ketone B13. Reduction of the ester group of compound B13 required a two step sequence. Thus, treating B13 with trimethyl orthoformate in the presence of tosic acid provides dienol ether B14, and then the ester of B14 is reduced with DIBALH in methylene chloride (CH2Cl2). If the work-up involves treatment with dilute hydrochloric acid, hydroxy-enone B15 is isolated. Addition of excess methyl Grignard to A3 gives tertiary alcohol B16. Careful removal of the silyl protecting group from B16 with tetrabutylammonium fluoride in tetrahydrofuran gives the desired diol B17. 
The C1 substituted steroid-4-en-3-ones of this invention may be prepared as depicted in Scheme C. The starting 1xcex1-alkylandrost-5-ene-3,17-diones (C19) are prepared from androsta-1,4-diene-3,17-dione (C18) according to Westermann and Nickisch (Westermann, J. and Nickisch, K., 1993, Angew. Chem. Int. Ed. Engl., 32, 1368-1370). The enone C19 is then protected as a dienol ether by treating C19 with trimethyl orthoformate in the presence of tosic acid. The resulting dienol ether C20 is reacted with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to give the vinyl fluoride C21. Diisobutylaluminum hydride reduction of the ester group in C21, followed by acid catalyzed hydrolysis of the dienol ether gives the desired 21-hydroxy-20"xgr"-fluoro-1xcex1-methylpregna-4,17(20)-dien-3-one (C23). Similar hydrolysis of the dienol ether C21 gives the corresponding 20"xgr"-fluoro-1xcex1-methyl-pregna-4,17(20)-dien-3-on-21-oic acid ethyl ester (C24).
The C1 substituted steroid-5-en-3-ols of this invention may be prepared as depicted in Scheme D. The starting material, 20"xgr"-fluoro-1xcex1-methylpregna4,17(20)-dien-3-on-21-oic acid ethyl ester (C24a), is first converted to the 3,5-dienol acetate D25a using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst. Reduction of the 3,5-dienol acetate moiety with sodium borohydride is known to give the corresponding 5-en-3-xcex2ol, which, in this case, affords compound D26a. Further reduction of D26a with diisobutylaluminum hydride gives 20"xgr"-fluoro-1xcex1-methylpregna-5,17(20)-diene-3xcex2,21-diol (D27a). Compounds D27b and D27c are prepared in similar manner.
The C2 substituted steroid-4-en-3-ones of this invention may be prepared as depicted in Scheme E. The known 2xcex1-methylandrost-4-ene-3,17-dione (E29a, Iriarte, J. and Ringold, H. J., 1958, Tetrahedron, 3, 28-36) and 2xcex1-ethylandrost-4-ene-3,17-dione (E29b, prepared by the methods of Ringold, H. J. and Rosenkranz, G., 1956, J. Org. Chem., 21, 1333-1335, and Tsuda, K. and Nozoe, S., 1959, Chem. Pharm. Bull. (Tokyo), 7, 232-237 and 238-240), serve as starting materials. Enone E29 is first protected as a dienol ether by treating E29 with trimethyl orthoformate in the presence of tosic acid. The resulting dienol ether E30 is reacted with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to give the vinyl fluoride ester E31. Diisobutylaluminum hydride reduction of the ester group, followed by acid catalyzed hydrolysis of the dienol ether gives the desired 21-hydroxy-20"xgr"-fluoro-2xcex1-alkylpregna-4,17(20)-dien-3-ones (E33a and E33b). Similar hydrolysis of the dienol ethers E31 gives the corresponding 20"xgr"-fluoro-2xcex1-alkylpregna-4,17(20)-dien-3-on-21-oic acid ethyl esters E34a and E34b. 
The C2 substituted steroid-5-en-3-ols of this invention may be prepared as depicted in Scheme F. The starting 20"xgr"-fluoro-2xcex1-alkylpregna4,17(20)-dien-3-on-21-oic acid ethyl esters (E34a-c) are converted to the 3,5-dienol acetates F35 using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst. Reduction of F35 with sodium borohydride gives the corresponding steroid-5-en-3-ols F36. Further reduction of F36 with diisobutylaluminum hydride and acid hydrolysis gives 20"xgr"-fluoro-2xcex1-methyl-pregna-5,17(20)-diene-3xcex2,21-diol (F37a), 20"xgr"-fluoro-2xcex1-ethylpregna-5,17(20)-diene-3xcex2,21-diol (F37b), 20"xgr"-fluoro-2xcex1-propylpregna-5,17(20)-diene-3xcex2,21-diol (F37c).
The C4 substituted steroid-4-en-3-ones of this invention may be prepared as depicted in Scheme G2. The starting point for the synthesis of each of these compounds is the appropriately substituted 4-alkytestosterone derivatives whose syntheses are detailed in Scheme G1. We found the most convenient route to these starting materials (G38) to be direct alkylation of testosterone (E28) by slow addition of alkyl iodide or alkyl bromide to a refluxing solution of testosterone and potassium t-butylate in t-butanol as described by Atwater (Atwater, N. W., J. Am. Chem. Soc., 1960, 82, 2847-2852). These compounds are also prepared by addition of an appropriate Grignard reagent to enol lactone G40 followed by Robinson annelation (see Sondheimer, F. and Mazur, Y., 1957, J. Amer. Chem. Soc., 79, 2906-2910). By this latter process the branched alkyl substituted steroid 17xcex2-hydroxy-4-(2-propyl)androst-4-en-3-one (G38c) is prepared. Jones oxidation of G38a-d provides 4-substituted steroid 4-en-3-ones G41a-d, respectively. 4-Chloroandrost-4-ene-3,17-dione (G41e) is prepared by reaction of androstenedione (G42) with sulfuryl chloride in pyridine as previously described (Kirk, D. N., Patel, D. K. and Petrow, V., J. Chem. Soc., 1956, 1184-1186; Mori, H., Chem. Pharm. Bull., 1962,10,429-432).
Transformation of the various 4-substituted steroid 4-en-3-ones G41a-e to vinyl fluorides G44a-e is shown in Scheme G2 and follows the general strategy previously developed. The steroid 4-en-3-one C41 is first protected as a dienol ether treating G41 with trimethyl orthoformate in the presence of tosic acid. The protected steroid G43 is then reacted with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to give the vinyl fluoride ester G44. Diisobutylaluminum hydride reduction of the ester group of G44, followed by acid catalyzed hydrolysis of the dienol ether gives the desired 21-hydroxy-204, -fluoro4-substituted-pregna-4,17(20)-dien-3-ones (G46a-e). Similar acid hydrolysis of the dienol ether moiety of vinyl fluoride esters G44a-e gives the corresponding 20"xgr"-fluoro-4-substituted-pregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (G47a-e).
The 4-nitro- and 4-aminosteroids (Scheme G3) are prepared using methodologies developed by Curran et al. (Curran, T. T., Flynn, G. A., Rudisill, D. E. and Weintraub, P. M., 1995, Tetrahedron Lett., 36, 4761-4764). By way of example, 20"xgr"-fluoro-21-hydroxy-1xcex1-methylpregna4,17(20)-dien-3-one (G48Aa) is reacted with t-butylate in t-butanol to form the thermodynamic enolate which then is reacted with i-propyl nitrate to give 20"xgr"-fluoro-21-hydroxy- 1xcex1-methyl-4-nitropregna-4,17(20)-dien-3-one (G49Aa). 20"xgr"-Fluoro-21-hydroxy-7xcex1-methyl-4-nitropregna-4,17(20)-dien-3-one (G49Ab) and 20"xgr"-fluoro-21-hydroxy-15xcex1-methyl-4-nitropregna-4,17(20)-dien-3-one (G49Ac) are prepared in an analogous manner. Chemoselective reduction of the nitro groups in G49Aa-c is accomplished by catalytic hydrogenation over Lindlar catalyst giving the corresponding amines: 4-amino-20"xgr"-fluoro-21-hydroxy-1xcex1-methylpregna-4,17(20)-dien-3-one (G50Aa), 4-amino-20"xgr"-fluoro-21-hydroxy-7xcex1-methylpregna-4,17(20)-dien-3-one (G50Ab) and 4-amino-20"xgr"-fluoro-21-hydroxy- 15xcex1-methylpregna-4,17(20)-dien-3-one (G50Ac), respectively. In the fashion just described, the 4-nitro-C21-esters G49Ba-c are prepared and transformed into the 4-amino-C21-esters G50Ba-c. 
The C4 substituted steroid-5-en-3-ols described in this invention may be prepared as depicted in Scheme H. Starting materials are the 4-alkyl- and 4-chloro-20"xgr"-fluoro-pregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (G47a-e) described in Scheme G2. As in the previous examples, the steroid 4-en-3-ones G47 are first converted to the 3,5-dienol acetates H51 using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst. Reduction of the 3,5-dienol acetates H51 to the corresponding 5-en-3-ols H52 is effected with sodium borohydride. Further reduction of H52 with diisobutylaluminum hydride gives the corresponding 20"xgr"-fluoro-4-substituted pregna-5,17(20)-diene-3xcex221-diols (H53a-e). 
The C6-alkylandrost-4-ene-3,17-diones (I56a-c) which serve as starting materials for the C6 substituted steroids of this invention are synthesized in five steps (the latter three steps are shown in Scheme I starting from I54) from androst-4-ene-3,17-dione using a method previously reported (Numazawa, M. and Oshibe, M. J. Med. Clem., 1994, 37, 1312-1319). After the C3 carbonyls of I56a-c are protected as dienol ethers I57a-c, a Wittig reaction is performed on the C17 ketones with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to give the vinyl fluoride esters I58a-c as mixtures of E- and Z-isomers. Diisobutylaluminum hydride reduction of the ester group of I58a-c followed by mild acid hydrolysis of the dienol ether protecting group of I59a-c affords the 20"xgr"-fluoro-6-substituted-pregna-4,17(20)-dien-21-ol-3-ones I60a-c. Acid catalyzed unmasking of the C3 carbonyl of I58a-c gives the corresponding 20"xgr"-fluoro-6-substituted-pregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (I61a-c). 
The C6 substituted steroid-5-en-3-ols described in this invention may be prepared as depicted in Scheme J. Starting materials are the 20"xgr"-fluoro-6-alkylpregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (I61a-c) described in Scheme I. As in the previous examples, the steroid 4-en-3-ones (I61a-c) are first converted to the 3,5-dienol acetates J62a-c using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst. Reduction of the 3,5-dienol acetates J62a-c to the corresponding 5-en-3-ols J63a-c is effected with sodium borohydride. After further reduction of J63a-c with diisobutylaluminum hydride there is obtained 20"xgr"-fluoro-6-substituted-pregna-5,17(20)-diene-3xcex2,21-diols J64a-c.
6-Dehydrotestosterone (K65) is converted to known C7-substituted steroids K66a-h (Grunwell, J. F., Benson, H. D., Johnston, J. O. and Petrow, V. Steroids, 1976, 27, 759-771), and oxidation of K66a-d and K66e-h with Jones reagent affords C7xcex1-alkylandrost-4-ene-3,17-diones (K67a-d) and C7xcex2-alkylandrost-4-ene-3,17-diones (K67e-h), respectively. The C3 carbonyls are protected as dienol ethers K68a-h (see Scheme K). Wittig reaction on the C17 ketones of dienol ethers K68a-h with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base gives the vinyl fluoride esters K69a-h as mixtures of E- and Z-isomers. Reduction of the dienol esters K69a-h with diisobutylaluminum hydride and acidic removal of the C3 protecting group gives 20"xgr"-fluoro-7-substituted-pregna-4,17(20)-dien-21-ol-3-ones K71a-h. Finally, acid catalyzed unmasking of the C3 carbonyl of K69a-h gives the desired 20"xgr"-fluoro-7-substituted-pregna-4,17(20)-dien-3-on-21-oic acid ethyl esters K72a-h. 
Scheme L outlines the syntheses of C7 substituted steroid-5-en-3-ols. The selectively C3 protected C7xcex1-alkylandrost-5-en-3,17-diols (L76a-d) and C7xcex2-alkylandrost-5-en-3,17-diols (L76e-h) are synthesized from the known C7 substituted steroids L74a-h (Grunwell, J. F., Benson, H. D., Johnston, J. O. and Petrow, V. Steroids, 1976, 27, 759-771) by borohydride reduction of L74a-h to give L75a-h. Protection of the C3 hydroxyl group as the t-butyidimethylsilyl ether with t-butyldimethylsilyl chloride in dimethylformamide and removal of the acetate moiety by saponification with lithium hydroxide in aqueous methanol/tetrahydrofuran gives 3xcex2-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-7-substituted-androst-5-en-17xcex2-ols (L76a-h). Oxidation of C17 alcohols L76a-h with Jones reagent gives the corresponding ketones L77a-h. The latter undergo Wittig reaction at the C17 ketone with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to afford the vinyl fluoride esters L78a-h as mixtures of E- and Z-isomers. Reduction of the ester groups with diisobutylaluminum hydride and tetrabutylammonium fluoride catalyzed removal of the C3 silyl group gives the 20"xgr"-fluoro-7-substituted-pregna-5,17(20)-diene-3xcex2,21-diols L80a-h. 
3xcex2-Hydroxyandrosta-5,15-dien-17-one (Scheme M, M81) is prepared by the method of Reeder and Joannou (Reeder, A. Y. and Joannou, G. E., Steroids, 1996, 61, 74-81) and used as starting material for the preparation steroids containing an additional double bond at C15 as shown in Scheme M. Alcohol M81 is first silylated by reaction with t-butyldimethylsilyl chloride to give silyl ether M82. Wittig reaction on the C17 ketone with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base gives vinyl fluoride ester M83 as a mixture of E- and Z-isomers. Reduction of ester M83 with diisobutylaluminum hydride in dichloromethane gives a mixture of alcohols which are separated by flash chromatography into the individual E- and Z-isomers M85 and M84, respectively. Removal of the silyl protecting group of Z-olefin M84 with tetrabutylammonium fluoride gives diol M86. Similar removal of the silyl protecting group of E-olefin M85 gives diol M87. 
The C15-alkyl-androst-5-en-17-ones (Scheme N, N88a-c), which serve as starting materials for the C15 substituted steroids of this invention, are synthesized in two steps from 3xcex2-hydroxyandrost-5,15-dien-17-ones M81 as shown in Scheme N. Wittig reaction on C17 ketones N88a-c with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base gives vinyl fluoride esters N89a-c as mixtures of E- and Z-isomers. Diisobutyl aluminum hydride reduction of the ester group of N89a-c gives alcohols N90a-c that on subsequent tetrabutylammonium fluoride catalyzed removal of the silyl protecting groups affords the 20"xgr"-fluoro-15-substituted-pregna-5,17(20)-diene-3xcex2,21-diols N91a-c.
Silyl protected 19-nordehydroepiandrosterone (Scheme O, O97) is prepared in five steps from the known 19-nortestosterone (O92) by modification of the method of Campbell and Babcock (Campbell, J. A. and Babcock, J. C., 1971, U.S. Pat. No. 3,597,418) wherein the C3 hydroxyl group is protected with a t-butyldimethylsilyl group rather than a tetrahydropyranyl group. Thus, alcohol O94 is prepared as described in U.S. Pat. No. 3,597,418 and is treated with t-butyldimethylsilyl chloride as previously described herein to give silyl ether O95. The C17 acetate is hydrolyzed with potassium carbonate in aqueous methanol, and resulting alcohol O96 is oxidized with pyridinium chromate to C17 ketone O97. Introduction of the vinyl fluoride via Wittig reaction as previously described herein affords vinyl fluoride ester O98. Reduction of O98 with diisobutylaluminum hydride and fluoride catalyzed removal of the silyl protecting group of O99 provides the desired diol O100 as a mixture of E and Z isomers. 